Elucidating the basic neurobiology of energy homeostasis is paramount in the prevention and treatment of obesity and type II diabetes. Drugs that increase the activity of central serotonin (5-hydroxytryptamine, 5-HT) have been widely used as appetite suppressants. However, these drugs often elicit unwanted side effects because they target multiple 5-HT pathways and receptors. A notable example is d-fenfluramine (d-Fen), a drug that blocks the reuptake of 5-HT and stimulates its release. In the mid-1990's, d-Fen was prescribed to millions of people in the United States for weight loss, frequently in combination with the sympathomimetic phentermine, but was withdrawn from clinical use in 1997 by the Food and Drug Administration due to reports of adverse cardiopulmonary events. The purpose of this proposal is to delineate the central nervous system (CNS) pathways through which drugs such as d-Fen selectively mediate their effects on food intake. We have strong preliminary data indicating that these drugs exert their effect on energy homeostasis by engaging melanocortin pathways. These central melanocortin pathways, through the melanocortin-4 receptors (MC4-Rs), have potent effects on metabolic-hormonal, neuroendocrine, and behavioral parameters associated with energy balance. In this proposal, we will assess whether 5-HT drugs selectively affect energy homeostasis through a necessary downstream activation of MC4-Rs. We propose a model of the mechanism of serotonergic drug action in which activation of specific serotonergic receptors increases the release of the endogenous MC4-R agonist alpha-melanocyte stimulating hormone (alpha-MSH) and inhibits the release of the endogenous antagonist agouti related peptide (AgRP). We will determine whether serotonergic diet drugs require functional downstream MC4-Rs to exert their effect. We offer a series of behavioral, physiological, genetic, and electrophysiological experiments to test components of our model. Data generated from this proposal have the potential to not only delineate the interaction between two key pathways regulating energy homeostasis, but to also identify a promising and very selective target for the prevention and treatment of obesity and type II diabetes.